sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients

Fane, Mitchell; Ecker, Brett L.; Kaur, Amanpreet; Marino, Gloria E.; Alicea, Gretchen M.; Douglass, Stephen M.; Chhabra, Yash; Webster, Marie R.; Marshall, Andrea; Colling, Richard; Espinosa, Olivia; Coupe, Nicholas; Maroo, Neera; Campo, Leticia; Middleton, Mark R.; Corrie, Pippa; Xu, Xiaowei; Karakousis, Giorgos C.; Weeraratna, Ashani T.

doi:10.1158/1078-0432.ccr-20-0446

Cited by 21 publications

(19 citation statements)

References 46 publications

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“…The immune-mobilizing monoclonal TCRs against cancer (ImmTACs) target TCR-presenting antigens, and recruits effector cells [ 52 ]. A proof of concept of this approach was given with tebentafusp, a TCR/Anti-CD3 bispecific fusion protein targeting gp100, which was able to induce responses in melanoma patients, including difficult to treat uveal melanoma [ 53 ].…”

Section: Opportunities To Overcome the Challengesmentioning

confidence: 99%

CAR-T cells and BiTEs in solid tumors: challenges and perspectives

et al. 2021

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Chimeric antigen receptor (CAR)-modified T cells and BiTEs are both immunotherapies which redirect T cell specificity against a tumor-specific antigen through the use of antibody fragments. They demonstrated remarkable efficacy in B cell hematologic malignancies, thus paving the way for their development in solid tumors. Nonetheless, the use of such new drugs to treat solid tumors is not straightforward. So far, the results from early phase clinical trials are not as impressive as expected but many improvements are under way. In this review we present an overview of the clinical development of CAR-T cells and BiTEs targeting the main antigens expressed by solid tumors. We emphasize the most frequent hurdles encountered by either CAR-T cells or BiTEs, or both, and summarize the strategies that have been proposed to overcome these obstacles.

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Section: Opportunities To Overcome the Challengesmentioning

confidence: 99%

CAR-T cells and BiTEs in solid tumors: challenges and perspectives

et al. 2021

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“…Inhibition of angiogenesis by using bevacizumab has achieved little impact on CM patient survival [ 139 , 140 ]. In the AVAST-M trial patients with resected stage IIB, IIC and III CM that received adjuvant bevacizumab showed improved disease-free interval but not overall survival (OS) [ 141 ].…”

Section: Cutaneous Melanomamentioning

confidence: 99%

“…In the AVAST-M trial patients with resected stage IIB, IIC and III CM that received adjuvant bevacizumab showed improved disease-free interval but not overall survival (OS) [ 141 ]. Nevertheless, in a recent study, Fane and colleagues, based on the observation that VEGF was expressed at higher level in older CM patients, re-analysed data from the AVAST-M trial finding an age-related difference in response to bevacizumab [ 139 ]. Although VEGF was decreased during aging, thereby reducing response to bevacizumab, angiogenesis was increased because of an increase of Secreted Frizzled Related Protein 2 (sFRP2), a modulator of Wnt signalling, in the aged tumor microenvironment [ 139 ].…”

Section: Cutaneous Melanomamentioning

confidence: 99%

“…Nevertheless, in a recent study, Fane and colleagues, based on the observation that VEGF was expressed at higher level in older CM patients, re-analysed data from the AVAST-M trial finding an age-related difference in response to bevacizumab [ 139 ]. Although VEGF was decreased during aging, thereby reducing response to bevacizumab, angiogenesis was increased because of an increase of Secreted Frizzled Related Protein 2 (sFRP2), a modulator of Wnt signalling, in the aged tumor microenvironment [ 139 ]. A phase 2 trial of bevacizumab and high-dose interferon alpha-2b (IFN-α2b) was performed in metastatic CM, demonstrating 24% RECIST (Response Evaluation Criteria in Solid Tumors) response and 20% stabilization of disease [ 142 ].…”

Section: Cutaneous Melanomamentioning

confidence: 99%

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Hypoxia-dependent drivers of melanoma progression

D’Aguanno

Mallone

Marenco

et al. 2021

J Exp Clin Cancer Res

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Hypoxia, a condition of low oxygen availability, is a hallmark of tumour microenvironment and promotes cancer progression and resistance to therapy. Many studies reported the essential role of hypoxia in regulating invasiveness, angiogenesis, vasculogenic mimicry and response to therapy in melanoma. Melanoma is an aggressive cancer originating from melanocytes located in the skin (cutaneous melanoma), in the uveal tract of the eye (uveal melanoma) or in mucosal membranes (mucosal melanoma). These three subtypes of melanoma represent distinct neoplasms in terms of biology, epidemiology, aetiology, molecular profile and clinical features.In this review, the latest progress in hypoxia-regulated pathways involved in the development and progression of all melanoma subtypes were discussed. We also summarized current knowledge on preclinical studies with drugs targeting Hypoxia-Inducible Factor-1, angiogenesis or vasculogenic mimicry. Finally, we described available evidence on clinical studies investigating the use of Hypoxia-Inducible Factor-1 inhibitors or antiangiogenic drugs, alone or in combination with other strategies, in metastatic and adjuvant settings of cutaneous, uveal and mucosal melanoma.Hypoxia-Inducible Factor-independent pathways have been also reported to regulate melanoma progression, but this issue is beyond the scope of this review.As evident from the numerous studies discussed in this review, the increasing knowledge of hypoxia-regulated pathways in melanoma progression and the promising results obtained from novel antiangiogenic therapies, could offer new perspectives in clinical practice in order to improve survival outcomes of melanoma patients.

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“…Still, anti-angiogenic monotherapy, although improving disease-free interval (DFI), did not prove to have durable and substantial anti-tumor activity in CM [ 92 ]. Additionally, VEGF decreases during aging leading to a poorer response in older compared to young patients treated with anti-VEGF inhibitors such as bevacizumab [ 93 ]. VEGF is reported to contribute to ICI resistance in mice by reducing CTL trafficking into the TME whilst favoring Treg infiltration through the permeable endothelium [ 94 ].…”

Section: Potential Of Anti-angiogenic Immunotherapy In CM Treatmentmentioning

confidence: 99%

Advances in Targeting Cutaneous Melanoma

Kasakovski

Skrygan

Gambichler

et al. 2021

Cancers

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To date, the skin remains the most common cancer site among Caucasians in the western world. The complex, layered structure of human skin harbors a heterogenous population of specialized cells. Each cell type residing in the skin potentially gives rise to a variety of cancers, including non-melanoma skin cancer, sarcoma, and cutaneous melanoma. Cutaneous melanoma is known to exacerbate and metastasize if not detected at an early stage, with mutant melanomas tending to acquire treatment resistance over time. The intricacy of melanoma thus necessitates diverse and patient-centered targeted treatment options. In addition to classical treatment through surgical intervention and radio- or chemotherapy, several systemic and intratumoral immunomodulators, pharmacological agents (e.g., targeted therapies), and oncolytic viruses are trialed or have been recently approved. Moreover, utilizing combinations of immune checkpoint blockade with targeted, oncolytic, or anti-angiogenic approaches for patients with advanced disease progression are promising approaches currently under pre-clinical and clinical investigation. In this review, we summarize the current ‘state-of-the-art’ as well as discuss emerging agents and regimens in cutaneous melanoma treatment.

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sFRP2 Supersedes VEGF as an Age-related Driver of Angiogenesis in Melanoma, Affecting Response to Anti-VEGF Therapy in Older Patients

Abstract: SFRP2 supersedes VEGF as an age-related driver of angiogenesis in melanoma,affecting response to anti-VEGF therapy in older patients.

Cited by 21 publications

References 46 publications

CAR-T cells and BiTEs in solid tumors: challenges and perspectives

CAR-T cells and BiTEs in solid tumors: challenges and perspectives

Hypoxia-dependent drivers of melanoma progression

Advances in Targeting Cutaneous Melanoma

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